As a trained psychiatrist and neuroscientist, the candidate has an ongoing commitment to increase knowledge about the molecular biology of complex behavior and to improve the treatment options for substance abuse disorders and related major psychiatric illness. The candidate intends to apply innovative methods of genetic recombination and large scale gene expression screening to animal models of substance abuse and psychosis. The long-term goal of these studies is to clarify the role of nerve growth factor molecules for drug-induced neuronal plasticity and addiction behavior at different stages of postnatal and adult life and to describe, on a large scale, neurotrophin- and drug-of-abuse mediated changes in genomic expression patterns. At the core of the candidate's project is the controlled manipulation of gene expression for two neurotrophic factors that are thought to be key regulators of synaptic plasticity in the reward structures: neurotrophin-3 (NT-3) and brain derived neurotrophic factor (BDNF). These growth factors and their receptors are expressed at high levels in some parts of the reward circuitry such as the nucleus accumbens (NAc) and the monoaminergic cell groups of the mid- and hindbrain. This proposal will induce controlled deletions of NT-3 and BDNF in the developing and in the adult brain, by using the P1 phage derived Cre/lox recombination system and a tetracycline-regulatable gene expression system. The resulting functional alterations in the brain's reward circuitry will be assessed on the molecular, the cellular and the behavioral level. Comparative studies will be conducted in mice with a controlled overexpression of NT-3 in the reward circuitry. Is orderly function of the reward circuitry dependent on neurotrophic factors? Are neurotrophins involved in the molecular mechanisms mediating addiction behavior and drug-related reinforcement? What are the molecular and cellular adaptations in the brain's reward systems in response to the induced changes in neurotrophin gene expression? The answer to these questions will be of major importance for a further understanding of the molecular biology of substance abuse disorders.